Bone fracture is a condition where a physiological continuity of bone tissue is partially or completely broken off and generally classified on the basis of the outbreak mechanism into (a) fracture by external force, (b) pathological fracture, and (c) fatigue fracture. In addition, the state of bone fracture is classified on the basis of the fracture line (the line tracing the epiphysis generated by bone transection), into fissure fracture, greenstick fracture, transverse fracture, oblique fracture, spiral fracture, segmental fracture, comminuted fracture, avulsion fracture, compression fracture, depression fracture, and the like (IGAKU-DAIJITEN, 18th ed., pp. 719-720, published by Nanzando).
Generally, it takes a considerable time until a bone fracture heals, which can be an obstacle in daily life. Further, the number of bone fracture of the osteoporosis patients, which is one of pathological fractures, has markedly increased with the aging of population. In particular, the transcervical fracture requires a long-term hospitalization and often develops internal complication including dementia due to a long-term hospitalization, which is becoming a major social and economic issue.
The fracture healing process is mainly classified into the following three stages (“Kossetsu Chiryougaku (Fracture Therapeutics)”, April, 2000, pp. 29-37, 46-51, Nanko-do), and it is considered that, the healing progresses in the reparative phase, an important stage for bone fracture healing, by a mechanism different from that in the bone remodeling phase where osteogenesis and osteolysis (bone resorption) occur repeatedly.    (1) An inflammatory phase: tissue surrounding bone is damaged, a fracture crevice is occupied with hematoma, and inflammation arises at the fracture region.    (2) A reparative phase: two processes progress in parallel; a process in which hematoma in the fracture crevice is removed yielding granulation tissue, soft callus is formed and gradually replaced by hard callus via osteogenic mechanism (endochondral ossification), and a process in which a new bone is formed by osteogenic cells present in periost (fibrous/intramembraneous ossification).    (3) A re-molding phase: the formed new bone extends for a long term by repeating the bone resorption and the bone formation, while the bone deformation is corrected and defect region reinforced.
The new bone formed during the re-molding phase has intensity of certain degree, and one's daily life is less hampered; however, the reparative phase takes a long term and restricts patient's daily life greatly. Accordingly, it is clinically important to shorten the term of reparative phase.
As substances accelerating bone fracture healing, there have been disclosed peptide-type physiologically active substances such as bone morphogenetic protein (BMP) and transforming growth factor (TGF) (Proc. Natl. Acad. Sci., USA, vol. 87, pp. 2220-2224 (1989). Further, it has been disclosed a pharmaceutical preparation for local administration containing a compound of the formula below (JP-04-364179A (1992)) as a bone formation accelerator after microcapsulation with lactic acid-glycolic acid copolymer (PLGA) in JP-09-263545A (1997).

The possibility of improving the bone mass by increasing the intracellular cyclic AMP (cAMP) level with phosphodiesterase (PDE) inhibitor was studied, and it was reported that the increase of bone mineral density of the backbone and the femur, and hyperplasia of cortical bone were observed in a mouse received daily subcutaneous injection of Pentoxifylline, a general PDE inhibitor, or Rolipram that is a selective PDE4 inhibitor (Bone, vol. 27, 6th issue, pp. 811-817 (2000)).
However, the researches above are focused on the pharmacological effect on a normal region, which is an osteogenic region during re-modeling process, and not a bone fracture region and are totally silent about bone fracture healing accelerating activity of PDE4 inhibitor.